1. Field of the Invention
The present invention relates to methods of treatment using ranolazine or another piperazine derivative compound of Formula I, particularly to methods of using ranolazine for treatment of tissues experiencing a physical or chemical insult, and specifically to methods of treating cardioplegia, hypoxic and/or reperfusion injury to cardiac or skeletal muscle or brain tissue, and for use in transplants.
2. Background Information
Ranolazine, i.e., .+-.N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-pipe razine acetamide or 1-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-4-[(2,6-dimethylphenyl)aminocarbo nylmethyl]piperazine, and the dihydrochloride salt thereof, and the compounds of Formula I, are described in U.S. Pat. No. 4,567,264, incorporated herein by reference. Ranolazine is disclosed as a calcium entry blocking compound useful in the treatment of cardiovascular diseases, such as, myocardial infarction, congestive heart failure, angina and arrhythmia.
The anti-ischemic effects of ranolazine have been described in a number of publications, such as, Jain et al., "A PRELIMINARY STUDY OF A NEW ANTI-ANGINAL AGENT", Cardiovascular Drugs and Therapy, Vol. 1, No. 3, p. 252 (October 1987); Allely and Alps, "THE EFFECTS OF THE NOVEL ANTI-ANGINAL AGENT ANOLAZINE (I.D.) IN A CANINE MODEL OF TRANSIENT MYOCARDIAL ISCHAEMIA", Br. J. Pharmacol., 1988, 93, 246P; and by Ferrandon et al., PROTECTIVE EFFECTS OF THE NOVEL ANTI-ISCHAEMIC AGENT RANOLAZINE (RS-43285) IN PERFUSED RAT HEARTS", Br. J. Pharmacol. , 1988, 93, 247P, where utility in protecting hearts from the potentially lethal biochemical and functional injury produced by ischaemia and/or reperfusion was reported. Tissue protection, however, is not achieved by a calcium entry blockade nor by a beta-blockade mechanism (Brown et al., Br. J. Pharmacol., 1988, 93, 248P), nor would such active agents be expected to have a tissue protective effect. Moreover, cardiodepression has been identified as a limiting factor for extensive use of CEBs in the treatment of cardio-related ischaemic conditions (Packer, et al., Circn., 75(V), 56-64, 1987; Barjon, et al., J. Am. Coll. Cardiol., 622-630, 1987).